Structure and mechanism of oxalate transporter OxlT in an oxalate-degrading bacterium in the gut microbiota.

An oxalate-degrading bacterium in the gut microbiota absorbs food-derived oxalate to use this as a carbon and energy source, thereby reducing the risk of kidney stone formation in host animals. The bacterial oxalate transporter OxlT selectively uptakes oxalate from the gut to bacterial cells with a strict discrimination from other nutrient carboxylates. Here, we present crystal structures of oxalate-bound and ligand-free OxlT in two distinct conformations, occluded and outward-facing states. The ligand-binding pocket contains basic residues that form salt bridges with oxalate while preventing the conformational switch to the occluded state without an acidic substrate. The occluded pocket can accommodate oxalate but not larger dicarboxylates, such as metabolic intermediates. The permeation pathways from the pocket are completely blocked by extensive interdomain interactions, which can be opened solely by a flip of a single side chain neighbouring the substrate. This study shows the structural basis underlying metabolic interactions enabling favourable symbiosis.

Incidence and appropriate management of drug-induced interstitial lung disease in Japanese patients with unresectable pancreatic cancer: A multicenter retrospective study.

AIM: Drug-induced interstitial lung disease (DI-ILD) is a serious adverse event during chemotherapy. This study aimed to obtain real-world data of the incidence, clinical characteristics, predictive factors, and prognosis of patients with pancreatic cancer who developed DI-ILD. METHODS: In patients with locally advanced or metastatic pancreatic cancer who underwent standard chemotherapy at our hospital and its participating facilities between April 2014 and March 2019, the clinical features, occurrence rate and clinical course of DI-ILD, and prognosis were retrospectively evaluated. RESULTS: Altogether, 390 patients were finally enrolled. DI-ILD occurred in 24 cases (6.2%). The median period from diagnosis of pancreatic cancer to the onset of DI-ILD was 2.2 months (.6-13.3 months). The rate of DI-ILD onset according to each regimen was 5.8% of gemcitabine (GEM) plus albumin-bound paclitaxel therapy (18/308), 3.8% of GEM (4/106), and 2.3% of FOLFIRINOX (2/88). The incidence of DI-ILD in GEM-based regimens was significantly higher than that in non-GEM-based regimens (p < .01). The median overall survival (OS) of the patients with and without DI-ILD after propensity score matching was 11.5 months and 11.4 months (p = .99), respectively. After the resolution of DI-ILD, no statistical significance in the median OS of the patients with and without subsequent treatment (11.0 vs. 6.8 months, p = .18) was observed. CONCLUSION: DI-ILD is not a rare adverse event in the current standard chemotherapy for pancreatic cancer in Japan. With appropriate management of DI-ILD, the prognosis of patients with DI-ILD can be equivalent to that of patients without DI-ILD.

The Glasgow Prognostic Score and stricture site can predict prognosis after endoscopic duodenal stent placement for malignant gastric outlet obstruction.

Endoscopic duodenal stent (DS) placement for malignant gastric outlet obstruction (GOO) is rapidly increasing in clinical practice; however, the most suitable patient candidates for DS placement have not been determined. One hundred and thirty-five patients with GOO who underwent DS placement in three Japanese referral centers between January 2010 and October 2019 were retrospectively evaluated. Overall survival (OS) after DS placement, technical/clinical success rates, adverse events, and predictive factors affecting OS after DS placement were also analyzed. The median OS after DS placement of all patients was 81 (7-901) days. Technical and clinical success rates were 99.3% and 83.7%, respectively. The GOO Scoring System score significantly increased before and after DS placement (0.9 vs. 2.7, P < 0.001). The procedure-related complication rate was 6.0%. All 19 patients (14.1%) with stent occlusion underwent endoscopic re-intervention successfully. Multivariate analyses revealed chemotherapy after DS placement (P = 0.01), stricture site in D3 (distal part of the papilla) (P = 0.01), and a Glasgow Prognostic Score (GPS) of 0-1 before duodenal stent placement (P < 0.001) were factors significantly associated with prolonged OS. In conclusion, patients with a GPS of 0-1 and D3 stricture who are tolerant of chemotherapy are suitable candidates for DS placement.

Natural history and clinical outcomes of pancreatic neuroendocrine neoplasms based on the WHO 2017 classification; a single-center experience of 30 years.

BACKGROUND/OBJECTIVES: This single-center study aimed to evaluate treatment outcomes and long-term prognosis of patients with pancreatic neuroendocrine neoplasms (PanNENs) based on the World Health Organization (WHO) 2017 classification. METHODS: We enrolled 245 patients with PanNENs treated at Kyushu University Hospital between January 1987 and March 2018. PanNENs were categorized according to the WHO 2017 classification or further subdivisions of Ki-67 index. Clinicopathological features, median survival time (MST), and prognostic factors were retrospectively analyzed. RESULTS: The number of PanNENs, especially non-functioning PanNENs, has increased over the last decade. The mean MST of all patients was 202 months; which was longest in patients with NET G1 (n = 145, MST = 261 months) relative to NET G2 (n = 72, 132 months), NET G3 (n = 3, 34 months) and NEC G3 (n = 17, 9 months). Prognosis in patients with surgery as the first-line treatment was significantly better than in those with drug therapy. However, 26% of patients who underwent curative resection developed recurrence after a median time of 28.7 months. In unresectable PanNENs (n = 97), the MST and 5-year survival rate were 78 months and 55.8%, respectively. Poor differentiation, Ki-67 index of >10% and presence of liver metastasis were significant unfavorable predictors. Response to first-line therapy (stable disease/partial response) and three or more treatment regimens were significant favorable predictors for unresectable PanNENs according to multivariate analyses (p < 0.01). CONCLUSIONS: We demonstrated the utility of the WHO 2017 classification for PanNENs in the real clinical setting. For better prognosis in PanNENs, the use of three or more regimens should be considered.